Intermediates and processes for the preparation of optically active octanoic acid derivatives

ABSTRACT

Novel intermediates, i.e., N-(2S-(2-propenyl)octanoyl)-(1S)-(−)-2,10-camphorsultam, N-(2S-(2-propynyl)octanoyl)-(1S)-(−)-2,10-camphorsultam and N-(2R-(2-propyl)octanoyl)-(1S)-(−)-2,10-camphorsultam; processes for the preparation of the intermediates; and processes for the preparation of optically active 2S-(2-propenyl)octanoic acid, 2S-(2-propynyl)octanoic acid and 2R-propyloctanoic acid by using the same. Optically active 2R-propyloctanoic acid equivalent or superior to that prepared by the process of the prior art in optical purity can be efficiently prepared in shorter reaction steps.

This application is a 371 of PCT/JP99/02427 filed May 11, 1999.

TECHNICAL FIELD

The present invention relates to novel intermediates, processes for thepreparation thereof and processes for the preparation of opticallyactive octanoic acid derivatives by using intermediates.

More particularly, the present invention relates to novel intermediates,i.e., N-(2S-(2-propenyl)octanoyl)-(1S)-(−)-2,10-camphorsultam,N-(2S-(2-propynyl) octanoyl)-(1S)-(−)-2,10-camphorsultam andN-(2R-(2-propyl)octanoyl)-(1S)-(−)-2,10-camphorsultam; processes for thepreparation thereof; and processes for the preparation of opticallyactive 2S-(2-propenyl)octanoic acid, 2S-(2-propynyl)octanoic acid and2R-propyloctanoic acid by using thereof intermediates.

BACKGROUND ART

The optically active octanoic acid derivatives prepared by the presentinvention are intermediates useful for the preparation of medicaments orare compounds useful as medicaments. For example, a racemate of2R-propyloctanoic acid is described in Example 7(33) of JP-A-7-316092 asan agent for treating or preventing neurodegenerative diseases derivedfrom functional abnormality of astrocytes.

As a result of the study after that, it was found that optically active2R-propyloctanoic acid has strong activities in particular. Accordingly,methods for obtaining this compound efficiently have been studiedvariously, and the following processes are known until now.

For example, JP-A-8-291106 discloses a method by optical resolutionusing optically active amine. However, in the process of opticallyseparating 2R-propyloctanoic acid from its racemate, both the chemicalyield (total synthetic yield of 5.9% at 6 stages from dimethylhexylmalonate) and the optically purity (90.0% e.e.) were soinsufficient that the process had no practical use.

A process using an optically active starting material is known as otherprocess for obtaining optically active 2R-propyloctanoic acid. Forexample, JP-A-8-295648 discloses a process using optically activeprolinol. An optically active branched alkanoic acid having a highoptical purity (96.0% e.e.) can be prepared using this process. However,the chemical yield (total synthetic yield of 20.1% at 5 stages frompentanoyl chloride) was so insufficient that the process did notnecessarily have a practical use.

DISCLOSURE OF THE INVENTION

The present inventor has found that novel intermediates, i.e.,N-(2S-(2-propenyl)octanoyl)-(1S)-(−)-2,10-camphorsultam,N-(2S-(2-propynyl)octanoyl)-(1S)-(−)-2,10-camphorsultam andN-(2R-(2-propyl)octanoyl)-(1S)-(−)-2,10-camphorsultam, by usingoptically active (1S)-(−)-2,10-camphorsultam, further processes for thepreparation of optically active 2S-(2-propenyl)octanoic acid,2S-(2-propynyl)octanoic acid and 2R-propyloctanoic acid as high opticalpurity (95-99% e.e.) by using thereof intermediates, accomplished thepresent invention.

That is, the present invention relates to novel intermediates, processesfor the preparation thereof and processes for the preparation ofoptically active octanoic acid derivatives by using intermediates asfollows:

[1] A compound ofN-(2S-(2-propenyl)octanoyl)-(1S)-(−)-2,10-camphorsultam,N-(2S-(2-propynyl)octanoyl)-(1S)-(−)-2,10-camphorsultam, orN-(2R-(2-propyl)octanoyl)-(1S)-(−)-2,10-camphorsultam;

[2] A compound ofN-(2S-(2-propenyl)octanoyl)-(1S)-(−)-2,10-camphorsultam depicted in [1];

[3] A compound ofN-(2S-(2-propynyl)octanoyl)-(1S)-(−)-2,10-camphorsultam depicted in [1];

[4] A compound of N-(2R-(2-propyl)octanoyl)-(1S)-(−)-2,10-camphorsultamdepicted in [1];

[5] A process for the preparation ofN-(2S-(2-propenyl)octanoyl)-(1S)-(−)-2,10-camphorsultam depicted in [2],which is characterized by the reaction ofN-octanoyl-(1S)-(−)-2,10-camphorsultam with allyl halide;

[6] A process for the preparation ofN-(2S-(2-propynyl)octanoyl)-(1S)-(−)-2,10-camphorsultam depicted in [3],which is characterized by the reaction ofN-octanoyl-(1S)-(−)-2,10-camphorsultam with propargyl halide;

[7] A process for the preparation ofN-(2R-(2-propyl)octanoyl)-(1S)-(−)-2,10-camphorsultam depicted in [4],which is characterized by the reduction ofN-(2S-(2-propenyl)octanoyl)-(1S)-(−)-2,10-camphorsultam depicted in [2];

[8] A process for the preparation ofN-(2R-(2-propyl)octanoyl)-(1S)-(−)-2,10-camphorsultam depicted in [4],which is characterized by the reduction ofN-(2S-(2-propynyl)octanoyl)-(1S)-(−)-2,10-camphorsultam depicted in [3];

[9] A process for the preparation of optically active2S-(2-propenyl)octanoic acid, which is characterized by the hydrolysisof N-(2S-(2-propenyl)octanoyl)-(1S)-(−)-2,10-camphorsultam depicted in[2];

[10] A process for the preparation of optically active 2R-propyloctanoicacid, which is characterized by the reduction of optically active2S-(2-propenyl)octanoic acid obtained in [9];

[11] A process for the preparation of optically active2S-(2-propynyl)octanoic acid, which is characterized by the hydrolysisof optically activeN-(2S-(2-propynyl)octanoyl)-(1S)-(−)-2,10-camphorsultam depicted in [3]

[12] A process for the preparation of optically active 2R-propyloctanoicacid, which is characterized by the reduction of optically active2S-(2-propynyl)octanoic acid obtained in [11].

[13] A process for the preparation of optically active 2R-propyloctanoicacid, which is characterized by the hydrolysis of optically activeN-(2R-(2-propyl)octanoyl)-(1S)-(−)-2,10-camphorsultam depicted in [4].

DETAILED EXPLANATION OF THE INVENTION

Optically active 2R-propyloctanoic acid in high optical purity (95-99%e.e.) and superior chemical yield (4 steps from octanoyl chloride, totalsynthetic yield 42.5-72.1%) can be efficiently prepared by the method ofthe present invention. Further the hydrolysis of camphorsultamderivatives by using tetraalkylammonium hydroxide is novel reaction.This observation has been confirmed from experiments by the presentinventor for the first time.

Novel intermediate compounds of the present invention can easily improveoptical purity by recrystallization since novel intermediates compoundsare easily crystallized. For example, the residue of the reaction waspurified by column chromatography to giveN-(2S-(2-propynyl)octanoyl)-(1S)-(−)-2,10-camphorsultam having 96.8%diastereoisomer excess (liquid chromatography). Further thus obtainedcompound could be improved to give it having 99.4% diastereoisomerexcess (liquid chromatography) by recrystallization.

In the present invention the process for the preparation of2R-propyloctanoic acid may be carried out four methods (A) to (D) asfollows, respectively.

(A) 2R-propyloctanoic acid may be prepared by reacting of camphorsultamwith octanoic acid or its derivatives→the reaction of allylhalide→hydrolysis →reduction;

1) reacting of (1S)-(−)-2,10-camphorsultam with octanoic acid or itsderivatives,

2) reacting of N-octanoyl-(1S)-(−)-2,10-camphorsultam with ally halide,

3) hydrolysis ofN-(2S-(2-propenyl)octanoyl)-(1S)-(−)-2,10-camphorsultam, and

4) reduction of optically active 2S-(2-propenyl)octanoic acid.

(B) 2R-propyloctanoic acid may be prepared by reacting of camphorsultamwith octanoic acid or its derivatives→the reaction of propargylhalide→hydrolysis→reduction;

1) reacting of (1S)-(−)-2,10-camphorsultam with octanoic acid or itsderivatives,

2) reacting of N-octanoyl-(1S)-(−)-2,10-camphorsultam with propargylhalide,

3) hydrolysis ofN-(2S-(2-propynyl)octanoyl)-(1S)-(−)-2,10-camphorsultam, and

4) reduction of optically active 2S-(2-propynyl)octanoic acid.

(C) 2R-propyloctanoic acid may be prepared by reacting of camphorsultamwith octanoic acid or its derivatives→the reaction of allylhalide→reduction →hydrolysis;

1) reacting of (1S)-(−)-2,10-camphorsultam with octanoic acid or itsderivatives,

2) reacting of N-octanoyl-(1S)-(−)-2,10-camphorsultam with ally halide,

3) reduction of N-(2S-(2-propenyl)octanoyl)-(1S)-(−)-2,10-camphorsultam,and

4) hydrolysis of N-(2S-(2-propyl)octanoyl)-(1S)-(−)-2,10-camphorsultam.

(D) 2R-propyloctanoic acid may be prepared by reacting of camphorsultamwith octanoic acid or its derivatives→the reaction of propargylhalide→reduction→hydrolysis;

1) reacting of (1S)-(−)-2,10-camphorsultam with octanoic acid or itsderivatives,

2) reacting of N-octanoyl-(1S)-(−)-2,10-camphorsultam with propargylhalide,

3) reduction of N-(2S-(2-propynyl)octanoyl)-(1S)-(−)-2,10-camphorsultam,and

4) hydrolysis of N-(2S-(2-propyl)octanoyl)-(1S)-(−)-2,10-camphorsultam.

The summary of the above four methods was shown in Scheme 1.

In the Scheme 1; X represent elimination group generally known (e.g.,p-toluenesulfonyl, methanesulfonyl, chloride, bromide or iodide atometc.).

The reaction of (1S)-(−)-2,10-camphorsultam with octanoic acid or itsderivatives is known per se (Tetrahedron, 48, 2453 (1992)), and may becarried out by, for example, using an acid halide.

The method using an acid halide may be carried out, for example, byreacting a octanoic acid with an acid halide (e.g., oxalyl chloride,thionyl chloride etc.) in an inert organic solvent (e.g., chloroform,dichloromethane, diethyl ether, tetrahydrofuran etc.) or without asolvent at from −20° C. to the reflux temperature of the solvent, andthen by reacting octanoyl chloride obtained with(1S)-(−)-2,10-camphorsultam in the presence of an base [tertiary amine(e.g., pyridine, triethylamine, dimethylaniline, dimethylaminopyridineetc.), hydroxide of an alkali metal (e.g., sodium hydroxide, potassiumhydroxide, etc.) or organic lithium (e.g., n-butyllithium, phenyllithiumetc.)] in an inert organic solvent (e.g., chloroform, dichloromethane,diethyl ether, tetrahydrofuran, dimethylformamide, dimethylsulfoxide,toluene etc.), at a temperature of from 0° C. to 40° C.,

This reaction preferably may be carried out in an atmosphere of inertgas (e.g., argon, nitrogen etc.) under anhydrous conditions.

The alkylation of N-octanoyl-(1S)-(−)-2,10-camphorsultam with alkylhalide or propagyl halide may be carried out by using organic metal. Thealkylation by using organic metal is known per se, and may be carriedout, for example, by reacting N-octanoyl-(1S)-(−)-2,10-camphorsultamwith allyl halide or propargyl halide in the presence or absence of aniodide of an alkali metal (e.g., lithium iodide, sodium iodide,potassium iodide, etc.) and in the presence of an base (e.g.,n-butyllithium, sec-butyllithium, t-butyllithium, phenyllithium,diisoporopyllithium, potassium hydroxide, sodium hydroxide, etc.) in aninert organic solvent (e.g., tetrahydrofuran, dioxane, diethyl ether,benzene, dimethoxyehtane, hexane, cyclohexane, hexamehtlphosphoramide,dimethylindazolidione or a mixture of them, etc.), at a temperature offrom −70° C. to 20° C.

The reduction of optically active 2S-(2-propenyl)octanoic acid,optically active 2S-(propynyl)octanoic acid,N-(2S-(2-propenyl)octanoyl)-(1S)-(−)-2,10-camphorsultam orN-(2S-(2-propynyl)octanoyl)-(1S)-(−)-2,10-camphorsultam may be carriedout by using catalytic reduction.

The catalytic reduction is known per se, and may be carried out, forexample, in an inert solvent (e.g., ethyl acetate tetrahydrofuran,tetrahydropyran, dioxane, diethoxyethane, diethyl ether, biphenyl ether,methanol, ethanol isopropanol, benzene, toluene, xylene, acetone, methylethyl ketone, phenyl methyl ketone, acetonitrile,hexamethylphosphoramide, dimethylformamide dimethylimizazolidine,mixture of them etc.), by using a catalyst (e.g., palladium on carbon,palladium, platinum, platinum oxide, nickel, palladium hydroxide oncarbon, rhodium, rhodium on carbon, ruthenium, ruthenium on carbon,tris(triphenylphosphine)chlororhodium, etc.) under an atmosphere ofhydrogen, at a temperature of from 0° C. to 60° C.

The hydrolysis ofN-(2S-(2-propenyl)octanoyl)-(1S)-(−)-2,10-camphorsultam,N-(2S-(2-propynyl)octanoyl)-(1S)-(−)-2,10-camphorsultam orN-(2S-(2-propyl)octanoyl)-(1S)-(−)-2,10-camphorsultam may be carried outby methods as follows.

(i) The hydrolysis by using hydroxide of an alkali metal is known per se(Tetrahedron, 43, 1969 (1987) or Helv. Chim. Acta., 72, 1337 (1989)),and may be carried out for example, in the presence or absence of aperoxide (e.g., hydroperoxide, t-butylhydroperoxide an aqueous solutionthem, etc.), by using hydroxide of an alkali metal (e.g., lithiumhydroxide, sodium hydroxide, potassium hydroxide, an aqueous solutionthem, etc.) in a water-miscible solvent (tetrahydrofuran, dioxane, amixture of water and them, etc.) at a temperature of from 0° C. to 40°C.

It is known that this reaction was proceeded without racemization andthe obtained compound was given to maintain optical purity.

(ii) The hydrolysis by using tetraalkylammonium hydroxide is quite novelreaction.

This reaction may be carried out, for example, in the presence orabsence of a peroxide (e.g., hydroperoxide, t-butylhydroperoxide anaqueous solution them, etc.) by using tetraalkylammonium hydroxide(e.g., tetrabutylammonium hydroxide, tetraoctylammonium hydroxide,tetradecylammonium hydroxide, an aqueous solution them, etc.) in awater-miscible solvent (tetrahydrofuran, dimethoxyethane, t-butanol,dioxane, a mixture of water and them, etc.) at a temperature of from−20° C. to 40° C. With the proviso that, when camphorsultam derivativeshave double or triple bond, this reaction may be carried out in thepresence of an excess amount of the compound having double bond (e.g.,2-methyl-2-butene, etc.) since the protection of the compound havingdouble or triple bond is oxidized by peroxide.

It is known that this reaction was proceeded without racemization andthe obtained compound was given to maintain optical purity.

Furthermore, optically active 2R-(2-propenyl)octanoic acid,2R-(2-propynyl)octanoic acid or 2S-propyloctanoic acid may be preparedby the same procedure as the method of the present invention using(1R)-(+)-2,10-camphorsultam instead of (1S)-(−)-2,10-camphorsultam.

N-(2S-(2-propenyl)octanoyl)-(1S)-(−)-2,10-camphorsultam,N-(2S-(2-propynyl)octanoyl)-(1S)-(−)-2,10-camphorsultam andN-(2R-(2-propyl)octanoyl)-(1S)-(−)-2,10-camphorsultam in the presentinvention are not described in the literature, therefore they are novelcompound. They are useful as intermediate of process for the preparationof 2R-propyloctanoic acid.

The racemate of 2S-(2-propenyl)octanoic acid as intermediate of thepresent invention is known per se, in the literature of Chem. Pharm.Bull., 24, 538 (1976). The racemate of 2S-(2-propynyl)octanoic acid isknown per se, in the literature of Tetrahedron Lett., 25, 5323 (1984).(1S)-(−)-2,10-camphorsultam is known per se, as the CAS registry No.94594-90-8. N-octanoyl-(1S)-(−)-2,10-camphorsultam is known per se, inthe literature of Tetrahedron, 48, 2453 (1992). 2S-(2-propynyl)octanoicacid is known per se, in JP-A-8-291106.

EXAMPLES

The present invention is explained in detail based on the followingexamples, but the present invention is not limited thereto.

EXAMPLE 1 Preparation of N-octanoyl-(1S)-(−)-2,10-camphorsultam

To a solution of (1S)-(−)-2,10-camphorsultam (15.0 g) in tetrahydrofuran(100 ml) was added triethylamine (14.6 ml) and dimethylaminopyridine(0.85 g). To this solution was added dropwise a solution of octanoylchloride (12.5 g) in tetrahydrofuran (20 ml) at 0° C. The reactionmixture was stirred for 1 hour at 0° C. To the mixture was added water(14 ml), and concentrated. The residue was diluted with ethyl acetate,washed with 2N aqueous solution of hydrochloric acid, water, a saturatedaqueous solution of sodium chloride (×2), 1 N aqueous solution of sodiumhydroxide (×2), water and a saturated aqueous solution of sodiumchloride, successively, dried over anhydrous magnesium sulfate, andconcentrated to give the title compound (24.0 g, 100% crude yield)having the following physical data.

TLC: Rf 0.33 (ethyl acetate:hexane=3:17); NMR (CDCl₃): δ 3.86 (1H, t,J=6.3 Hz), 3.49 (1H, d, J=13.2 Hz), 3.43 (1H, d, J=13.2 Hz), 2.72 (2H,dt, J=7.9, 2.6 Hz), 2.09 (2H, m), 1.88 (3H, m), 1.67 (2H, m), 1.31 (10H,m), 1.14 (3H, s), 0.96 (3H, s), 0.86 (3H, t, J=6.8 Hz); IR (liquidfilm): ν 2957, 2930, 2857, 1698, 1458, 1414, 1375, 1331, 1271, 1237,1217, 1165, 1134, 1109, 1065, 1040cm⁻¹.

EXAMPLE 2 Preparation ofN-(2S-(2-propenyl)octanoyl)-(1S)-(−)-2,10-camphorsultam

To a solution of diisopropylamine (20.0 ml) in tetrahydrofuran (40 ml)was added dropwise 1.6 M n-butyllithium in hexane solution (94 ml) at 0°C. The mixture was stirred for 30 minute at the same temperature. Thissolution was slowly added dropwise to the solution of the compoundprepared in reference example 1 (52.2 g) in tetrahydrofuran (80 ml) at−72° C. After the mixture was stirred for 30 minute at the sametemperature, and to this solution was added dropwise the mixturesolution of allyl bromide (18 ml), a solution of lithiumiodide (3.7 g)in tetrahydrofuran (15 ml) and dimethylindazolidione (23 ml). Thereaction mixture was stirred for 1 hour at −78° C., 4 hours at −20° C.and 1 hour at 0° C. The mixture was quenched by water, and concentrated.The residue was extracted with a mixture solution of hexane:ethylacetate=1:1. The extract was washed with 2N aqueous solution ofhydrochloric acid, water (×2), a saturated aqueous solution of sodiumhydrogencarbonate and a saturated aqueous solution of sodium chloride,successively, dried over anhydrous magnesium sulfate, and concentrated.The residue was recrystallized from methanol (×2) to give the titlecompound (37.4 g, 71.7% yield (2 steps from(1S)-(−)-2,10-camphorsultam)) having the following physical data.

TLC: Rf 0.45 (hexane:ethyl acetate=17:3); NMR (CDCl₃): δ 5.80 (1H, ddt,J=15.6, 9.8, 7.2 Hz), 5.05 (1H, ddt, J=15.6, 2.2 Hz), 4.98 (1H, dd,J=9.8, 2.2 Hz), 3.90 (2H, t, J=6.3 Hz), 3.51 (1H, d, J=13.9 Hz), 3.42(1H, d, J=13.9 Hz), 3.12 (1H, m), 2.36 (2H, t, J=7.0 Hz), 2.03 (2H, d,J=6.4 Hz), 1.88 (2H, m), 1.74 (1H, m), 1.26 (10H, m), 1.16 (3H, s), 0.96(3H, s), 0.86 (3H, t, J=6.4 Hz); IR (KBr): ν 3075, 2994, 2857, 1682,1640, 1471, 1445, 1418, 1401, 1327, 1291, 1273, 1252, 1238, 1217, 1167,1136, 1117, 1069, 1042, 992, 947, 909 cm⁻¹; m.p.: 94-95° C.;diastereoisomer excess: 99% (liquid chromatography).

EXAMPLE 3 Preparation of 2S-(2-propenyl)octanoic acid

To a solution of the compound prepared in example 2 (10.0 g) indimethoxyethane (10 ml) was added 2-methyl-2-butene (8.3 ml) and 30%aqueous solution hydrogen peroxide (5.4 ml) at −10° C. To vigorouslystirring this mixture was added dropwise 40% aqueous solutiontetrabutylammonium hydroxide (34 ml). The reaction mixture was stirredfor 2 hours. The mixture was quenched by 2N aqueous solution of sodiumsulfite (35 ml), and stirred for 1 hour at room temperature. To themixture was added 1N aqueous solution of oxalic acid, and the mixturewas extracted with a mixture solution of ethyl acetate:isopropylether=1:4. The extract was washed with 1N aqueous solution of oxalicacid, water (×2) and a saturated aqueous solution of sodium chloride,successively, dried over anhydrous sodium sulfate, and concentrated. Tothe residue was added a mixture solution of isopropyl ether andhexane=1:2, and insoluble matters were filtered. The filtrate wasconcentrated to give the title compound (5.72 g) having the followingphysical data.

TLC: Rf 0.46 (hexane:ethyl acetate=7:3); NMR (CDCl₃): δ 5.78 (1H, ddt,J=17.0, 10.1, 6.9 Hz), 5.10 (1H, dd, J=17.0, 1.9 Hz), 5.05 (1H, dd,J=10.1, 1.9 Hz), 2.44 (2H, m), 2.30 (1H, m), 1.64 (1H, m), 1.55 (1H, m),1.30 (8H, brs), 0.90 (3H, t, J=6.8 Hz); IR (neat): ν 2930, 2859, 1709,1644, 1460, 1420, 1289, 1250, 1210, 992, 916 cm⁻¹; Optical purity: 99%e.e. (gas chromatography).

EXAMPLE 4 Preparation of 2R-propyloctanoic acid

To the mixture solution of the compound prepared in example 3(a) (168mg) in methanol (1.2 ml) and ethyl acetate (1.2 ml) was added 10%palladium carbon (17 mg). The mixture was stirred for 1 hour at roomtemperature under an atmosphere of hydrogen gas. The reaction mixturewas filtrated through Celite (being on sale), and the filtrate wasconcentrated. The residue was purified by silica gel columnchromatography (hexane: ethyl acetate=9:1→4:1) to give the titlecompound (109 mg, 74% yield (2 steps from the compound prepared inexample 2)) having the following physical data.

TLC: Rf 0.46 (hexane:ethyl acetate=7:3); NMR (CDCl₃): δ 2.38 (1H, m),1.55 (2H, m), 1.53-1.20 (12H, m), 0.94 (3H, t, J=6.8 Hz), 0.90 (3H, t,J=6.8 Hz); IR (neat): ν 2959, 2932, 1707, 1470, 1420, 1379, 1289, 1215,943 cm⁻¹; Optical purity:95.2% e.e. (liquid chromatography).

EXAMPLE 5 Preparation ofN-(2R-(2-propyl)octanoyl)-(1S)-(−)-2,10-camphorsultam

To 10% palladium carbon (500 mg, containing 60.7% in water) was addedthe mixture solution of the compound prepared in example 2 (2.0 g) inethylacetate (7 ml) and dimethoxyethane (7 ml). The mixture was stirredfor 1 hour at room temperature under an atmosphere of hydrogen gas. Thereaction mixture was filtrated through Celite (being on sale), and thefiltrate was concentrated. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate=9:1) to give the title compound(2.01 g, 100% yield) as a solid having the following physical data.

TLC: Rf 0.37 (hexane:ethyl acetate=9:1); NMR (CDCl₃): δ 3.90 (1H, t,J=6.3 Hz), 3.51 (1H, d, J=13.2 Hz), 3.43 (1H, d, J=13.2 Hz), 3.01, (1H,m), 2.07 (2H, m), 1.88 (3H, m), 1.77-1.19 (16H, m), 1.16 (3H, s), 0.97(3H, s), 0.89 (3H, t, J=6.8 Hz), 0.83 (3H, t, J=6.8 Hz); IR (KBr): ν2959, 2861, 1684, 1468, 1458, 1416, 1401, 1375, 1327, 1281, 1278, 1250,1237, 1165, 1136, 1113, 1062, 1040cm⁻¹; diastereoisomer excess: 99%(liquid chromatography).

EXAMPLE 6 Preparation of 2R-propyloctanoic acid

To a 40% aqueous solution of tetrabutylammonium hydroxide (1.4 ml) wasadded dimethoxyethane (2 ml) and toluene (2 ml), and concentrated. Afterthis procedure was repeated (×4), anhydrous tetrabutylammonium hydroxidewas prepared. To a solution of the compound prepared in example 5 (400mg) in tetrahydrofuran (2 ml) was added dropwise 30% aqueous solutionhydrogen peroxide (0.21 ml) and a solution of anhydroustetrabutylammonium hydroxide (the prepared in above) in tetrahydrofuran(2 ml) at −20° C. The reaction mixture was stirred for 50 minute at −20°C. The mixture was quenched by 1.5N aqueous solution of sodium sulfite(1.4 ml), and stirred for 30 minute at room temperature. The mixture wasconcentrated, water and 2N aqueous solution of hydrochloric acid wasadded thereto, and the mixture was extracted with a mixture solution ofethyl acetate:isopropyl ether=1:4 (×2). The extract was washed withwater (×2) and a saturated aqueous solution of sodium chloride,successively, dried over anhydrous sodium sulfate, and concentrated. Tothe residue was added isopropyl ether, insoluble matters were filtered,and the filtrate was concentrated. The residue was purified by silicagel column chromatography (hexane:ethyl acetate=19:1) to give the titlecompound (115 mg, 59.3% yield) having the following physical data.

TLC: Rf 0.46 (hexane:ethyl acetate=7:3); NMR (CDCl₃): δ 2.38 (1H, m,),1.55 (2H, m), 1.53-1.20 (12H, m), 0.94 (3H, t, J=6.8 Hz), 0.90 (3H, t,J=6.8 Hz); IR (neat): ν 2959, 2932, 1707, 1470, 1420, 1379, 1289, 1215,943 cm⁻¹; Optical purity:99% e.e. (liquid chromatography).

EXAMPLE 7 Preparation ofN-(2S-(2-propynyl)octanoyl)-(1S)-(−)-2,10-camphorsultam

To a solution of diisopropylamine (6.7 ml) in tetrahydrofuran (13 ml)was added dropwise 1.6 M n-butyllithium in hexane solution (32 ml) at 0°C. The mixture was stirred for 20 minute at the same temperature. Thissolution was slowly added dropwise to the solution of the compoundprepared in reference example 1 (16.0 g) in tetrahydrofuran (27 ml) at−78° C. After the mixture was stirred for 30 minute at the sametemperature, and to this solution was added dropwise the mixturesolution of propargyl bromide (5.2 ml), a solution of lithiumiodide(1.24 g) in tetrahydrofuran (5 ml) and dimethylindazolidione (7.6 ml).The reaction mixture was stirred for 1.5 hours at −78° C. and 2 hours at−30° C. The mixture was quenched by water, and concentrated. The residuewas extracted with a mixture solution of hexane:ethyl acetate=1:1. Theextract was washed with a saturated aqueous solution of sodium ammonium(×2), water (×3) and a saturated aqueous solution of sodium chloride,successively, dried over anhydrous sodium sulfate, and concentrated. Theresidue was purified by silica gel column chromatography (hexane: ethylacetate=19:1→9:1) to give the title compound (14.6 g, 83.0% yield (2steps from (1S)-(−)-2,10-camphorsultam) having the following physicaldata.

TLC Rf 0.55 (toluene:ethyl acetate=19: 1); NMR (CDCl₃): δ 3.93 (1H, dd,J=7.1, 5.4 Hz), 3.53 (1H, d, J=13.9 Hz), 3.45 (1H, d, J=13.9 Hz), 3.21(1H, m), 2.55 (2H, m), 2.11 (2H, m), 1.99 (1H, t, J=2.6 Hz), 1.87 (4H,m), 1.57-1.23 (11H, m), 1.19 (3H, s), 0.98 (3H, s), 0.87 (3H, t, J=6.7Hz); IR (KBr): ν 3318, 2970, 2945, 2850, 1690, 1470, 1458, 1433, 1418,1397, 1323, 1280, 1270, 1238, 1220, 1165, 1134, 1110, 1061, 1040, 947cm⁻¹; diastereoisomer excess: 96.8% (liquid chromatography).

Thus obtained title compound was recrystallized from a mixture solutionof isopropyl alcohol: water=5:1 to give the title compound having thefollowing physical data. diastereoisomer excess: 99.4% (liquidchromatography).

EXAMPLE 8(a) Preparation of 2S-(2-propynyl)octanoic acid

To a solution of the compound prepared in example 7[400 mg,diastereoisomer excess: 96.8% (liquid chromatography)] indimethoxyethane (4 ml) was added 2-methyl-2-butene (0.33 ml) and 30%aqueous solution hydrogen peroxide (0.22 ml). To vigorously stirringthis mixture was added dropwise 40% aqueous solution tetrabutylammoniumhydroxide (1.4 ml). The reaction mixture was stirred for 10 minute at−10° C. The mixture was quenched by 1.5N aqueous solution of sodiumsulfite (1.5 ml), and stirred for 30 minute at room temperature. Themixture was concentrated, water was added thereto, and the mixture wasextracted with a mixture solution of ethyl acetate: isopropyl ether=1:4(×2). To the water layer was added 2N aqueous solution of hydrochloricacid, and the mixture was extracted with isopropyl ether (×2). Theextract was washed with water (×2) and a saturated aqueous solution ofsodium chloride, successively, dried over anhydrous sodium sulfate, andconcentrated. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate=9:1) to give the title compound(172 mg, 89.6% yield) having the following physical data.

TLC: Rf 0.55 (toluene:ethyl acetate=19:1); NMR (CDCl₃): δ 2.62 (1H, m),2.54 (1H, ddd, J=16.6, 6.8, 2.6 Hz), 2.43 (1H, ddd, J=16.6, 6.8, 2.6Hz), 2.03 (1H, t J=2.6 Hz), 1.70 (2H, m), 1.30 (8H, m), 0.90 (3H, t,J=6.8 Hz); IR (neat): ν 3312, 2930, 1717, 1559, 1541, 1509, 1458, 1289,938 cm⁻¹; Optical purity:96.4% e.e. (gas chromatography).

EXAMPLE 8(b) Preparation of 2S-(2-propynyl)octanoic acid

To a mixture solution of the compound prepared in example 7[400 mg,diastereoisomer excess: 96.8% (liquid chromatography)] intetrahydrofuran (16 ml) and water (2.6 ml) was added dropwise 30%aqueous solution hydrogen peroxide (0.22 ml) at 0° C. To this solutionwas added dropwise 2N aqueous solution of lithium hydroxide (2.1 ml).The reaction mixture was stirred for 2 hours at −10° C. and 1.5 hours atroom temperature.

The mixture was quenched by 1.5N aqueous solution of sodium sulfite (5.6ml), and stirred for 3 hours at room temperature. The mixture wasconcentrated, water was added thereto, and the mixture was extractedwith a mixture solution of ethyl acetate:isopropyl ether=1:4 (×2). Theextract was washed with water (×3) and a saturated aqueous solution ofsodium chloride. To all water layer was added 2N aqueous solution ofhydrochloric acid, and the mixture was extracted with isopropyl ether(×2). The extract was washed with water (×2) and a saturated aqueoussolution of sodium chloride, successively, dried over anhydrous sodiumsulfate, and concentrated. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate=9:1) to give the title compound(169 mg, 88% yield) having the following physical data.

TLC: Rf 0.55 (toluene:ethyl acetate=19:1); NMR (CDCl₃): δ 2.62 (1H, m),2.54 (1H, ddd, J=16.6, 6.8, 2.6 Hz), 2.43 (1H, ddd, J=16.6, 6.8, 2.6Hz), 2.03 (1H, t J=2.6 Hz), 1.70 (2H, m), 1.30 (8H, m), 0.90 (3H, t,J=6.8 Hz); IR (neat): ν 3312, 2930, 1717, 1559, 1541, 1509, 1458, 1289,938 cm⁻¹; Optical purity:96.8% e.e. (gas chromatography).

EXAMPLE 9(a) Preparation of 2R-propyloctanoic acid

To a solution of the compound prepared in example 8(a) (114 mg) in ethylacetate (2 ml) was added palladium carbon (10 mg). The reaction mixturewas stirred for 10 minute at room temperature under an atmosphere ofhydrogen gas. The reaction mixture was filtrated through Celite (beingon sale), and concentrated. The residue was purified by silica gelcolumn chromatography (hexane:ethyl acetate=9:1→4:1) to give the titlecompound (113 mg, 97% yield) having the following physical data.

TLC: Rf 0.34 (hexane:ethyl acetate=4:1); NMR (CDCl₃): δ 2.46-2.27 (1H,m), 1.75-1.12 (14H, m), 0.96-0.75 (6H, m); IR (neat): ν 2959, 2932,2860, 1708, 1466, 1419, 1380, 1290, 1255, 1217, 1112, 944 cm⁻¹.

EXAMPLE 9(b) Preparation of 2R-propyloctanoic acid

To a solution of the compound prepared in example 8(a) [3.0 g, 99.3%e.e. (liquid chromatography)] in diethoxyethane (75 ml) was added 5%palladium carbon (600 mg, 50% containing in water). The reaction mixturewas stirred for 1 hour under an atmosphere of hydrogen gas and 5atmospheric pressure, further stirred for 4 hours at 30° C. The reactionmixture was cooled down at room temperature, filtrated through Celite(being on sale), and the filtrate was concentrated. The residue wasdissolved in the mixture solution of hexane:ethyl acetate=5:1, andextracted with 2N aqueous solution of sodium hydroxide. To the waterlayer was added conc. hydrochloric acid, and the mixture was extractedwith the mixture solution of hexane:ethyl acetate=5:1. The extract waswashed with water and a saturated aqueous solution of sodium chloride,successively, dried over anhydrous magnesium sulfate, and concentratedto give the title compound (2.7 g, 89% yield) having the followingphysical data.

TLC: Rf 0.34 (hexane:ethyl acetate=4:1); Optical purity:96.8% e.e.(liquid chromatography).

INDUSTRIAL APPLICATION FIELD

According to the present invention, optically active 2R-propyloctanoicacid or its preparation intermediate compounds can be obtained asmedicaments at an optical purity equal to or higher than that of theconventional processes and at few reaction steps efficiently.

Specifically, 2R-propyloctanoic acid is obtained at 90.0% e.e. (theprocess of JP-A-8-291106) or 96.0% e.e. (the process of JP-A-8-295648)in the conventionally know processes, whereas it is obtained at a highoptical purity of 95-99% e.e. in the process of the present invention.

Furthermore, in the preparation of optically active 2R-propyloctanoicacid, the process of the present invention is by far more excellent thanthe conventional processes in terms of the chemical yield and the numberof the reaction steps. Specifically, the total synthetic yield is 5.9%at 6 stages from dimethyl hexylmalonate (the process of JP-A-8-291106)and the total synthetic yield is 20.1% at 5 stages from pentanoylchloride (the process of JP-A-8-295648) in the conventional processes,whereas 2R-propyloctanoic acid can be obtained at a high chemical yieldof a total synthetic yield of 42.5-72.1% and by few step numbers of 4stages from octanoyl chloride.

As discussed above, the process of the present invention would be aprocess suitable for synthesizing 2R-propyloctanoic acid industrially ata large scale.

What is claimed is:
 1. A compound ofN-(2S-(2-propenyl)octanoyl)-(1S)-(−)-2,10-camphorsultam,N-(2S-(2-propynyl)octanoyl)-(1S)-(−)-2,10-camphorsultam, orN-(2R-(2-propyl)octanoyl)-(1S)-(−)-2,10-camphorsultam.
 2. A compoundaccording to claim 1, which isN-(2S-(2-propenyl)octanoyl)-(1S)-(−)-2,10-camphorsultam.
 3. A compoundaccording to claim 1, which isN-(2S-(2-propynyl)octanoyl)-(1S)-(−)-2,10-camphorsultam.
 4. A compoundaccording to claim 1, which isN-(2R-(2-propyl)octanoyl)-(1S)-(−)-2,10-camphorsultam.
 5. A process forthe preparation ofN-(2S-(2-propenyl)octanoyl)-(1S)-(−)-2,10-camphorsultam, which comprisesreacting N-octanoyl-(1S)-(−)-2,10-camphorsultam with allyl halide.
 6. Aprocess for the preparation ofN-(2S-(2-propynl)octanoyl)-(1S)-(−)-2,10-camphorsultam, which comprisesreacting N-octanoyl-(1S)-(−)-2,10-camphorsultam with propargyl halide.7. A process for the preparation ofN-(2R-(2-propyl)octanoyl)-(1S)-(−)-2,10-camphorsultam, which comprisesreducing N-(2S-(2-propenyl)octanoyl-(1S)-(−)-2,10-camphorsultam.
 8. Aprocess for the preparation ofN-(2R-(2-propyl)octanoyl)-(1S)-(−)-2,10-camphorsultam, which comprisesreducing N-(2S-(2-propynyl)octanoyl-(1S)-(−)-2,10-camphorsultam.